Systems and methods for stimulating cellular function in tissue

ABSTRACT

The invention generally relates to systems and methods for stimulating cellular function in biological tissue. In certain embodiments, the invention provides a method for stimulating cellular function within tissue that involves providing a first type of energy to a region of tissue, in which the first type is provided in an amount that inhibits cellular function within the region of tissue, and providing a second type of energy to the region of tissue, in which the second type is provided in an amount that facilitates cellular function within the region of tissue, wherein the combined effect stimulates cellular function within the tissue.

GOVERNMENT SUPPORT

This invention was made with Government support under Grant NumberR43NS062530 awarded by the National Institute of Neurological Disordersand Stroke (NINDS) of the National Institute of Health (NIH) andContract No. W31P4Q-09-C-0117 awarded by Defense Advanced ResearchProjects Agency (DARPA). The Government has certain rights in thisinvention.

FIELD OF THE INVENTION

The invention generally relates to systems and methods for stimulatingcellular function in biological tissue.

BACKGROUND

Stimulation of tissue in humans and other animals is used in a number ofclinical applications as well as in clinical and general biologicalresearch. In particular, stimulation of neural tissue has been used inthe treatment of various diseases including Parkinson's disease,depression, and intractable pain. The stimulation may be appliedinvasively, e.g., by performing surgery to remove a portion of the skulland implanting electrodes in a specific location within brain tissue, ornon-invasively, .e.g., transcranial direct current stimulation andtranscranial magnetic stimulation.

SUMMARY

The invention recognizes that a synergistic stimulation effect in aregion of tissue may be achieved by combining a first type of energythat is provided in an amount that inhibits cellular function with asecond type of energy that is provided in an amount that facilitatescellular function. Data herein show that the stimulatory effect isgreater than the summed effect of the first and second amounts of energyprovided to the region of tissue.

Accordingly, methods of the invention involve providing a first type ofenergy to a region of tissue, in which the first type is provided in anamount that inhibits cellular function within the region of tissue, andproviding a second type of energy to the region of tissue, in which thesecond type is provided in an amount that facilitates cellular functionwithin the region of tissue, wherein the combined effect stimulatescellular function within the tissue. In certain embodiments, thestimulatory effect is facilitatory to the cellular function within thetissue. In other embodiments, the stimulatory effect is inhibitory tothe cellular function within the tissue. The first and second types ofenergy may be provided simultaneously or sequentially.

Any energy sources known in the art may be used with systems of theinvention. In certain embodiments, the first energy source is anelectric source that produces an electric field. The electric filed maybe pulsed, time varying, pulsed a plurality of time with each pulsebeing for a different length of time, or time invariant. In certainembodiments, the second energy source is a source that produces amechanical field, such as an ultrasound device. The mechanical filed maybe pulsed, time varying, or pulsed a plurality of time with each pulsebeing for a different length of time. In certain embodiments, theelectric field and/or the mechanical field is focused. The otherpermutations are also attainable, where the effect direction (i.e.,inhibitory or facilitatory) is dependent on the electrical and/orultrasound source transducer parameters and/or the electrical and/orultrasound field parameters.

The first and second energy sources may be applied to any tissue. Incertain embodiments, the first and second energy sources are applied toa structure or multiple structures within the brain or the nervoussystem such as the dorsal lateral prefrontal cortex, any component ofthe basal ganglia, nucleus accumbens, gastric nuclei, brainstem,thalamus, inferior colliculus, superior colliculus, periaqueductal gray,primary motor cortex, supplementary motor cortex, occipital lobe,Brodmann areas 1-48, primary sensory cortex, primary visual cortex,primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves,cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe,sub-cortical structures, and spinal cord. In particular embodiments, thetissue is neural tissue, and the affect of the stimulation alters neuralfunction past the duration of stimulation.

Another aspect of the invention provides a system for stimulatingcellular function within tissue that includes an ultrasound deviceconfigured to emit a mechanical field that inhibits cellular functionwithin the region of tissue, and an electric source configured to emitan electric field that facilitates cellular function within the regionof tissue, the system being configured such that the ultrasound deviceand the electric source target the same region of tissue and thecombined effect stimulates cellular function in a facilitatory mannerwithin the region of tissue. Similarly, the ultrasound source could beprovided in a facilitatory manner and the electrical source in aninhibitory manner such that the overall effect on cellular function isinhibitory. The other permutations are also attainable, where the effectdirection (i.e., inhibitory or facilitatory) is dependent on theelectrical and/or ultrasound source transducer parameters and/or theelectrical and/or ultrasound field parameters.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned and other features and objects of this invention,and the manner of attaining them, will become more apparent and theinvention itself will be better understood by reference to the followingdescription of embodiments of the invention taken in conjunction withthe accompanying drawings, wherein:

FIG. 1 is a plan view of one embodiment of an apparatus for stimulatingbiological tissue constructed in accordance with the principles of thepresent disclosure;

FIG. 2 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue constructed in accordance with theprinciples of the present disclosure;

FIG. 3 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue implementing a chemical source foraltering permittivity constructed in accordance with the principles ofthe present disclosure;

FIG. 4 is a top plan view of an exemplary embodiment of an apparatus forstimulating biological tissue implementing a radiation source foraltering permittivity constructed in accordance with the principles ofthe present disclosure; and

FIG. 5 is a top plan view of another exemplary embodiment of anapparatus for stimulating biological tissue implementing an optical beamfor altering permittivity constructed in accordance with the principlesof the present disclosure.

FIGS. 6A-C show a set of graphs comparing mechanical stimulation alone,electrical stimulation alone, and the combination of mechanical andelectrical stimulation. Part A is a raw data example of visual evokedpotentials (VEPs) shown from one animal, and one electrode contact (forreadability). Part B demonstrates the stimulation effect (averagedacross all contacts and animals). Part C demonstrates the depth effectof stimulation (the electrode implemented had 23 contacts (50 mm length,and 50 mm inter-contact distance), but in FIG. 3-C only 3 contacts areshown for readability). Throughout the figure, * indicates significance,which was determined first by an N-way Anova, as explained in theexamples section, with a subsequent multiple comparison of means (withLSD correction).

DETAILED DESCRIPTION

It is envisioned that the present disclosure may be used to stimulatebiological tissue in-vivo comprising an electric source that is placedon and/or in the body to generate an electric field and a means foraltering the permittivity of tissue relative to the electric field,whereby the alteration of the tissue permittivity relative to theelectric field generates a displacement current in the tissue. Theexemplary embodiments of the apparatuses and methods disclosed can beemployed in the area of neural stimulation, where amplified, focused,direction altered, and/or attenuated currents could be used to alterneural activity via directly stimulating neurons, depolarizing neurons,hyperpolarizing neurons, modifying neural membrane potentials, alteringthe level of neural cell excitability, and/or altering the likelihood ofa neural cell firing. Likewise, the method for stimulating biologicaltissue may also be employed in the area of muscular stimulation,including cardiac stimulation, where amplified, focused, directionaltered, and/or attenuated currents could be used to alter muscularactivity via direct stimulation, depolarizing muscle cells,hyperpolarizing muscle cells, modifying membrane potentials, alteringthe level of muscle cell excitability, and/or altering the likelihood ofcell firing. Similarly, it is envisioned that the present disclosure maybe employed in the area of cellular metabolism, physical therapy, drugdelivery, and gene therapy. Furthermore, stimulation methods describedherein can result in or influence tissue growth (such as promoting bonegrowth, directing neural growth or regeneration, and/or interfering witha tumor).

Detailed embodiments of the present disclosure are disclosed herein,however, it is to be understood that the described embodiments aremerely exemplary of the disclosure, which may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art tovariously employ the present disclosure in virtually any appropriatelydetailed embodiment.

The components of the tissue stimulation method according to the presentdisclosure are fabricated from materials suitable for a variety medicalapplications, such as, for example, polymerics, gels, films, and/ormetals, depending on the particular application and/or preference.Semi-rigid and rigid polymerics are contemplated for fabrication, aswell as resilient materials, such as molded medical grade polyurethane,as well as flexible or malleable materials. The motors, gearing,electronics, power components, electrodes, and transducers of the methodmay be fabricated from those suitable for a variety of medicalapplications. The method according to the present disclosure may alsoinclude circuit boards, circuitry, processor components, etc. forcomputerized control. One skilled in the art, however, will realize thatother materials and fabrication methods suitable for assembly andmanufacture, in accordance with the present disclosure, also would beappropriate.

The following discussion includes a description of the components andexemplary methods for generating currents in biological tissues inaccordance with the principles of the present disclosure. Alternateembodiments are also disclosed. Reference will now be made in detail tothe exemplary embodiments of the present disclosure illustrated in theaccompanying figures wherein like reference numerals indicate thesimilar parts throughout the figures.

Turning now to FIG. 1, which illustrates an exemplary embodiment of anapparatus 10 to alter currents, e.g., amplify, focus, alter direction,and/or attenuate in the presence of an applied electric field or appliedcurrent source by the combined application of a mechanical field withina biological material to stimulate the biological cells and/or tissue inaccordance with the present disclosure. For example, the apparatus 10illustrated in FIG. 1 according to the present disclosure may be appliedto the area of neural stimulation. An initial source electric field 14results in a current in the tissue. The electric field 14 is created byan electric source, current or voltage source. As described in furtherdetail below, the permittivity of the tissue is altered relative to theelectric field, for example by a mechanical field, thereby generating anadditional displacement current.

Electrodes 12 are applied to the scalp and generate a low magnitudeelectric field 14 over a large brain region. While electrodes 12 areused and applied to the scalp in this exemplary embodiment, it isenvisioned that the electrodes may be applied to a number of differentareas on the body including areas around the scalp. It is alsoenvisioned that one electrode may be placed proximal to the tissue beingstimulated and the other distant, such as one electrode on the scalp andone on the thorax. It is further envisioned that electric source couldbe mono-polar with just a single electrode, or multi-polar with multipleelectrodes. Similarly, the electric source may be applied to tissue viaany medically acceptable medium. It is also envisioned that means couldbe used where the electric source does not need to be in direct contactwith the tissue, such as for example, inductive magnetic sources wherethe entire tissue region is placed within a large solenoid generatingmagnetic fields or near a coil generating magnetic fields, where themagnetic fields induce electric currents in the tissue.

The electric source may be direct current (DC) or alternating current(AC) and may be applied inside or outside the tissue of interest.Additionally, the source may be time varying. Similarly, the source maybe pulsed and may be comprised of time varying pulse forms. The sourcemay be an impulse. Also, the source according to the present disclosuremay be intermittent.

A mechanical source such as an ultrasound source 16 is applied on thescalp and provides concentrated acoustic energy 18, i.e., mechanicalfield to a focused region of neural tissue, affecting a smaller numberof neurons 22 than affected by the electric field 14, by the mechanicalfield 18 altering the tissue permittivity relative to the appliedelectric field 14, and thereby generating the altered current 20. Themechanical source may be any acoustic source such as an ultrasounddevice. Generally, such device may be a device composed ofelectromechanical transducers capable of converting an electrical signalto mechanical energy such as those containing piezoelectric materials, adevice composed of electromechanical transducers capable of convertingan electrical signal to mechanical energy such as those in an acousticspeaker that implement electromagnets, a device in which the mechanicalsource is coupled to a separate mechanical apparatus that drives thesystem, or any similar device capable of converting chemical, plasma,electrical, nuclear, or thermal energy to mechanical energy andgenerating a mechanical field.

Furthermore, the mechanical field could be generated via an ultrasoundtransducer that could be used for imaging tissue. The mechanical fieldmay be coupled to tissue via a bridging medium, such as a container ofsaline to assist in the focusing or through gels and/or pastes whichalter the acoustic impedance between the mechanical source and thetissue. The mechanical field may be time varying, pulsed, an impulse, ormay be comprised of time varying pulse forms. It is envisioned that themechanical source may be applied inside or outside of the tissue ofinterest. There are no limitations as to the frequencies that can beapplied via the mechanical source, however, exemplary mechanical fieldfrequencies range from the sub kHZ to 1000s of MHz. Additionally,multiple transducers providing multiple mechanical fields with similaror differing frequencies, and/or similar or different mechanical fieldwaveforms may be used—such as in an array of sources like those used infocused ultrasound arrays. Similarly, multiple varied electric fieldscould also be applied. The combined fields, electric and mechanical, maybe controlled intermittently to cause specific patterns of spikingactivity or alterations in neural excitability. For example, the devicemay produce a periodic signal at a fixed frequency, or high frequencysignals at a pulsed frequency to cause stimulation at pulse frequenciesshown to be effective in treating numerous pathologies. Such stimulationwaveforms may be those implemented in rapid or theta burst TMStreatments, deep brain stimulation treatments, epidural brainstimulation treatments, spinal cord stimulation treatments, or forperipheral electrical stimulation nerve treatments. The ultrasoundsource may be placed at any location relative to the electrodelocations, i.e., within, on top of, below, or outside the same locationas the electrodes as long as components of the electric field andmechanical field are in the same region. The locations of the sourcesshould be relative to each other such that the fields intersect relativeto the tissue and cells to be stimulated, or to direct the currentalteration relative to the cellular components being stimulated.

The apparatus and method according to the present disclosure generatescapacitive currents via permittivity alterations, which can besignificant in magnitude, especially in the presence of low frequencyapplied electric fields. Tissue permittivities in biological tissues aremuch higher than most other non biological materials, especially for lowfrequency applied electric fields where the penetration depths ofelectric fields are highest. This is because the permittivity isinversely related to the frequency of the applied electric field, suchthat the tissue permittivity magnitude is higher with lower frequencies.For example, for electric field frequencies below 100,000 Hz, braintissue has permittivity magnitudes as high as or greater than 10̂8(100,000,000) times the permittivity of free space (8.854*10̂-12 faradper meter), and as such, minimal local perturbations of the relativemagnitude can lead to significant displacement current generation. Asthe frequency of the electric field increases, the relative permittivitydecreases by orders of magnitude, dropping to magnitudes ofapproximately 10̂3 times the permittivity of free space (8.854*10̂-12farad per meter) for electric field frequencies of approximately 100,000Hz. Additionally, by not being constrained to higher electric fieldfrequencies, the method according to the present disclosure is anadvantageous method for stimulating biological tissue due to loweredpenetration depth limitations and thus lowered field strengthrequirements. Additionally, because displacement currents are generatedin the area of the permittivity change, focusing can be accomplished viathe ultrasound alone. For example, to generate capacitive currents via apermittivity perturbation relative to an applied electric field asdescribed above, broad DC or a low frequency electric source field wellbelow the cellular stimulation threshold is applied to a brain regionbut stimulation effects are locally focused in a smaller region byaltering the tissue permittivity in the focused region of a mechanicalfield generated by a mechanical source such as an ultrasound source.This could be done noninvasively with the electrodes and the ultrasounddevice both placed on the scalp surface such that the fields penetratethe tissue surrounding the brain region and intersect in the targetedbrain location, or with one or both of the electrodes and/or theultrasound device implanted below the scalp surface (in the brain or anyof the surrounding tissue) such that the fields intersect in thetargeted region.

A displacement current is generated by the modification of thepermittivity in the presence of the sub threshold electric field andprovides a stimulatory signal. In addition to the main permittivitychange that occurs in the tissues, which is responsible for stimulation(i.e., the generation of the altered currents for stimulation), aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents. In a further embodiment, thedisplacement current generation and altered ohmic current components maycombine for stimulation. Generally, tissue conductivities vary slightlyas a function of the applied electric field frequency over the DC to100,000 Hz frequency range, but not to the same degree as thepermittivities, and increase with the increasing frequency of theapplied electric field. Additionally in biological tissues, unlike othermaterials, the conductivity and permittivity do not show a simpleone-to-one relationship as a function of the applied electric fieldfrequency. The permittivity ranges are as discussed above.

Although the process described may be accomplished at any frequency ofthe applied electric field, the method in an exemplary embodiment isapplied with lower frequency applied electric fields due to the fact thepermittivity magnitudes of tissues, as high as or greater than 10̂8 timesthe permittivity of free space, and the electric field penetrationdepths are highest for low frequency applied electric fields. Higherfrequency applied electric fields may be less desirable as they willrequire greater radiation power to penetrate the tissue and/or a morepronounced mechanical source for permittivity alteration to achieve thesame relative tissue permittivity change, i.e., at higher appliedelectric field frequencies the permittivity of the tissue is lower andas such would need a greater overall perturbation to have the sameoverall change in permittivity of a tissue as at a lower frequency.Applied electric field frequencies in the range of DC to approximately100,000 Hz frequencies are advantageous due to the high tissuepermittivity in this frequency band and the high penetration depth forbiological tissues at these frequencies. In this band, tissues arewithin the so called ‘alpha dispersion band’ where relative tissuepermittivity magnitudes are maximally elevated (i.e., as high as orgreater than 10̂8 times the permittivity of free space). Frequenciesabove approximately 100,000 to 1,000,000 Hz for the applied electricfields are still applicable for the method described in generatingdisplacement currents for the stimulation of biologic cells and tissue,however, both the tissue permittivity and penetration depth are limitedfor biological tissues in this band compared to the previous band butdisplacement currents of sufficient magnitude can still be generated forsome applications. In this range, the magnitude of the applied electricfield will likely need to be increased, or the method used to alter thepermittivity relative to the applied electric field increased to bringabout a greater permittivity change, relative to the tissue'spermittivity magnitude for the applied electric field frequency.Additionally, due to potential safety concerns for some applications, itmay be necessary to limit the time of application of the fields or topulse the fields, as opposed to the continuous application that ispossible in the prior band. For tissues or applications where the safetyconcerns preclude the technique in deeper tissues, the technique couldstill be applied in more superficial applications in a noninvasivemanner or via an invasive method. Higher frequency applied electricfields, above 1,000,000 to 100,000,000 Hz, could be used in generatingdisplacement currents for the stimulation of biologic cells and tissue.However, this would require a more sufficient permittivity alteration orelectromagnetic radiation, and as such is less than ideal in terms ofsafety than the earlier bands. For frequencies of the applied electricfield above 100,000,000 Hz, biologic cell and tissue stimulation maystill be possible, but may be limited for specialized applications thatrequire less significant displacement currents.

The focus of the electric and mechanical fields to generate an alteredcurrent according to the present disclosure may be directed to variousstructures within the brain or nervous system including but not limitedto dorsal lateral prefrontal cortex, any component of the basal ganglia,nucleus accumbens, gastric nuclei, brainstem, thalamus, inferiorcolliculus, superior colliculus, periaqueductal gray, primary motorcortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-48,primary sensory cortex, primary visual cortex, primary auditory cortex,amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontallobe, occipital lobe, temporal lobe, parietal lobe, sub-corticalstructures, spinal cord, nerve roots, sensory organs, and peripheralnerves.

The focused tissue may be selected such that a wide variety ofpathologies may be treated. Such pathologies that may be treated includebut are not limited to Multiple Sclerosis, Amyotrophic LateralSclerosis, Alzheimer's Disease, Dystonia, Tics, Spinal Cord Injury,Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving,Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson's Disease,Parkinsonianism, Obsessions, Depression, Schizophrenia, BipolarDisorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism,Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, AuditoryHallucinations, Movement Disorders, Neurodegenerative Disorders, PainDisorders, Metabolic Disorders, Addictive Disorders, PsychiatricDisorders, Traumatic Nerve Injury, and Sensory Disorders. Furthermore,electric and mechanical fields to generate an altered current may befocused on specific brain or neural structures to enact proceduresincluding sensory augmentation, sensory alteration, anesthesia inductionand maintenance, brain mapping, epileptic mapping, neural atrophyreduction, neuroprosthetic interaction or control with nervous system,stroke and traumatic injury neurorehabilitation, bladder control,assisting breathing, cardiac pacing, muscle stimulation, and treatmentof pain syndromes, such as those caused by migraine, neuropathies, andlow-back pain; or internal visceral diseases, such as chronicpancreatitis or cancer. The methods herein could be expanded to any formof arthritis, impingement disorders, overuse injuries, entrapmentdisorders, and/or any muscle, skeletal, or connective tissue disorderwhich leads to chronic pain, central sensitization of the pain signals,and/or an inflammatory response.

In the focused region of tissue to which the mechanical fields andelectrical fields are delivered, the excitability of individual neuronscan be heightened to the point that the neurons can be stimulated by thecombined fields, or be affected such as to cause or amplify thealteration of the neural excitability caused by the altered currents,either through an increase or decrease in the excitability of theneurons. This alteration of neural excitability can last past theduration of stimulation and thus be used as a basis to provide lastingtreatment. Additionally, the combined fields can be provided inmultiple, but separate sessions to have a summed, or carry-over effect,on the excitability of the cells and tissue. The combined fields can beprovided prior to another form of stimulation, to prime the tissuemaking it more or less susceptible to alternate, follow-up forms ofstimulation. Furthermore, the combined fields can be provided after analternate form of stimulation, where the alternate form of stimulationis used to prime the tissue to make it more or less susceptible to theform of stimulation disclosed herein. Furthermore, the combined fieldscould be applied for a chronic period of time.

FIG. 2 illustrates a set up 30 to perform a method for generating analtered current with a newly generated displacement current 32 forstimulation in biologic tissue 34 through the combined effects of anelectric field 36 and a mechanical field 38. A tissue or composite oftissues 34 is placed adjacent to the anode and cathode of an electricsource 40 which generates an electric field 36. The electric field 36 iscombined with a mechanical, e.g., ultrasound field 38 which can befocused on the tissue 34 and generated via an ultrasound transducer 42.In a sub-region of tissue 44 where the mechanical field 38 is focusedand intersects with the electric field 36, a displacement current 32 isgenerated. By vibrating and/or mechanically perturbing the sub-region oftissue 44, the permittivity of the tissue 44 can be altered relative tothe applied electric field 36 to generate a displacement current 32 inaddition to the current that would be present due to the source electricfield 36 and altered due to conductivity changes in the tissue caused bythe mechanical perturbation.

By providing the mechanical field 38 to the sub region of tissue 44, thepermittivity can be altered within the electric field 36 by either newelements of the sub region of tissue 44 vibrating in and out of theelectric field such that the continuum permittivity of the tissue ischanged relative to the electric field 36, or that the bulk propertiesof the sub region of tissue 44 and the permittivity, or tissuecapacitance, change due to the mechanical perturbation. An example ofaltering the permittivity within the electric field can occur when acell membrane and extra-cellular fluid, both of differentpermittivities, are altered in position relative to the electric fieldby the mechanical field. This movement of tissues of differentpermittivity relative to the electric field will generate a newdisplacement current. The tissues could have permittivity values as highas or greater than 10̂8 times the permittivity of free space, differ byorders of magnitude, and/or have anisotropic properties such that thetissue itself demonstrates a different permittivity magnitude dependingon the relative direction of the applied electric field. An example ofaltering permittivity of the bulk tissue occurs where the relativepermittivity constant of the bulk tissue is directly altered bymechanical perturbation in the presence of an electric field. Themechanical source, i.e., ultrasound source may be placed at any locationrelative to the electrode locations, i.e., within or outside the samelocation as the electrodes, as long as components of the electric fieldand mechanical field are in the same region.

Tissue permittivities can be altered relative to the applied electricfields via a number of methods. Mechanical techniques can be used toeither alter the bulk tissue permittivity relative to an appliedelectric field or move tissue components of differing permittivitiesrelative to an applied electric field. There are no specific limitationsto the frequency of the mechanical field that is applied as previouslydiscussed, however, exemplary frequencies range from the sub kHZ to1000s of MHz. A second electromagnetic field could be applied to thetissue, at a different frequency than the initial frequency of theapplied electromagnetic field, such that it alters the tissuepermittivity at the frequency dependent point of the initially appliedelectric field. An optical signal could also be focused on the tissuesto alter the permittivity of the tissue relative to an applied electricfield. A chemical agent or thermal field could also be applied to thetissues to alter the permittivity of the tissue relative to an appliedelectric field. These methods could also be used in combination to alterthe tissue permittivity relative to an applied electric field viainvasive or noninvasive methods.

For example, FIG. 3 shows a set up 50 for generating an altered currentwith a newly generated displacement current 52 through the combinedeffects of an electric field 54 and a chemical agent 56. A tissue orcomposite of tissues 58 is placed within an electric source 60 whichgenerates an electric field 54 and combined with chemical source 62which releases a chemical agent 56 that can be focused on the tissue 58.In the area that the chemical agent 56 is released in the tissue 64, theelectric field 54 transects the sub region of tissue 64, and thechemical agent 56 reacts with the sub region of tissue 64 to alter thetissue's relative permittivity relative to the applied electric field54. This generates a displacement current 52 in addition to the currentthat would be present due to the source electric field 54. The chemicalagent 56 may be any agent which can react with the tissue or cellularcomponents of the tissue 64 to alter its permittivity relative to theelectric field 54. This may be by a thermoreactive process to raise orlower the tissue 64 temperature or through a chemical reaction whichalters the distribution of ions in the cellular and extra-cellularmedia, for instance, along ionic double layers at cell walls in thetissue 64. Similarly, the conformation of proteins and other chargedcomponents within the tissue 64 could be altered such that thepermittivity of the tissue is altered relative to the low frequencyelectric field 54. The agent could also be any agent that adapts thepermanent dipole moments of any molecules or compounds in the tissue 64,temporarily or permanently relative to the low frequency electric field54. The chemical reaction driven by the chemical agent 56 must workrapidly enough such that the permittivity of the tissue is quicklyaltered in the presence of the electric field 54 in order to generatethe displacement current 52. The reaction may also be such as tofluctuate the permittivity, such that as the permittivity continues tochange displacement currents continue to be generated. In addition tothe main permittivity change that occurs in the tissues, a conductivitychange could also occur in the tissue, which secondarily alters theohmic component of the currents. A biological agent may be used in placeof, or in addition to, the chemical agent 56. This embodiment may haveparticular application for focused drug delivery where an additionalchemical or biological agent is included to assist in therapy of thetissue, or where the altered current could drive an additionalelectrochemical reaction for therapy. For example, this could be used inareas such as focused gene therapy or focused chemotherapy.

Another example is shown in FIG. 4, which illustrates a set up 70 forapplying a method for generating an altered current with a newlygenerated displacement current 72 through the combined effects of a lowfrequency electric field 74 and an electromagnetic radiation field 76. Atissue or composite of tissues 78 is placed within a low frequencyelectric field 74 which is generated by an electric source 80 andcombined with radiation source 82 which generates a radiation field 76that can be focused on the tissue 78. In the area that the radiationfield 76 is focused in the tissue 78, the electric field 74 transectsthe sub component of tissue 84, where the radiation field 76 interactswith the sub component of tissue 84 to alter the tissue's relativepermittivity relative to the applied electric field 74, and as suchgenerates a displacement current 72 in addition to the current thatwould be present due to the source electric field 74 or the radiationsource field 76 alone. The electromagnetic radiation field 76 could, forexample, interact with the tissue 84 by altering its temperature throughohmic processes, alter the distribution of ions in the cellular andextra-cellular media for instance along ionic double layers along cellwalls through the electric forces acting on the ions, or alter theconformation of proteins and other charged components within the tissuethrough the electric forces such that the permittivity of the tissue isaltered relative to the low frequency electric field 74. Furthermore,the electromagnetic field 76, could interact with the tissue 84 bymoving components of the tissue via electrorestrictive forces, as wouldbe seen in anisotropic tissues, to alter the continuum permittivity ofthe tissue relative to the low frequency electric field 74. In additionto the main permittivity change that occurs in the tissues, aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents.

FIG. 5 shows a set up 90 for applying a method for generating an alteredcurrent with a newly generated displacement current 92 through thecombined effects of an electric field 94 and an optical beam 96. Atissue or composite of tissues 98 is placed within electric field 94generated by an electric source 100 and combined with optical source 102which generates optical beam 96 that can be focused on the tissue 98. Inthe area that the optical beam 96 is focused on the tissue, the electricfield 94 transects the sub component of tissue 104, where the opticalbeam 96 reacts with the tissue to alter the tissue's relativepermittivity relative to the applied electric field 94, and as suchgenerates a displacement current 92 in addition to the current thatwould be present due to the source electric field 94. The optical beam96 could, for example, interact with the tissue by altering itstemperature through photothermal effects and/or particle excitation,alter the distribution of ions in the cellular and extra-cellular mediafor instance along ionic double layers along cell walls by exciting themovement of ions optically, ionizing the tissue via lasertissue-interactions, or alter the conformation of proteins and othercharged components within the tissue such that the permittivity of thetissue is altered relative to the low frequency electric field 94. Inaddition to the main permittivity change that occurs in the tissues, aconductivity change could also occur in the tissue, which secondarilyalters the ohmic component of the currents.

In another embodiment, a thermal source to alter the permittivity of thetissue may be used. In such embodiments, a thermal source such as aheating probe, a cooling probe, or a hybrid probe may be placed externalor internal to the tissue to be stimulated. A thermal source may alterthe permittivity of the tissue through the direct permittivitydependence of tissue temperature, mechanical expansion of tissues inresponse to temperature changes, or by mechanical forces that arise dueto altered particle and ionic agitation in response to the temperaturealteration such that permittivity of the tissue is altered relative toan applied electric field. In addition to the main permittivity changethat occurs in the tissues, a conductivity change could also occur inthe tissue, which secondarily alters the ohmic component of thecurrents. This embodiment may be useful for stimulation in the presenceof an acute injury to the tissue where the thermal source could be usedto additionally assist in the treatment of the tissue injury, forexample with a traumatic brain injury or an infarct in any organ such asthe heart. The tissue could be cooled or heated at the same timestimulation is provided to reduce the impact of an injury.

In a further embodiment, the method according to the present disclosureis applied in the area of muscular stimulation, where amplified,focused, direction altered, and/or attenuated currents could be used toalter muscular activity via direct stimulation, depolarizing muscularcells, hyperpolarizing muscular cells, modifying membrane potentials,and/or increasing or decreasing the excitability of the muscle cells.This alteration of excitability or firing patterns can last past theduration of stimulation and thus be used as a basis to provide lastingtreatment. Additionally, the stimulation can be provided in multiple,but separate sessions to have a summed, or carry-over effect, on theexcitability of cells and tissue. Additionally, the stimulation could beprovided to prime the tissue by adjusting the muscle cell excitabilityto make it more or less susceptible to alternate follow up forms ofstimulation. The stimulation could be used after another form ofstimulation was used to prime the tissue. Furthermore, the stimulationcould be applied for a chronic period of time. This embodiment may beuseful for altering or assisting cardiac pacing or function, assistedbreathing, muscle stimulation for rehabilitation, muscle stimulation inthe presence of nerve or spinal cord injury to prevent atrophy or assistin movement, or as substitution for physical exercise.

In yet another embodiment, the method according to the presentdisclosure can be applied the area of physical therapy, where amplified,focused, direction altered, and/or attenuated currents could be used tostimulate blood flow, increase or alter neuromuscular response, limitinflammation, speed the break down of scar tissue, and speedrehabilitation by applying the focus of the current generation to theeffected region in need of physical therapy. It is envisioned that themethod according to the present disclosure may have a wide variety inthe area of physical therapy including the treatment or rehabilitationof traumatic injuries, sports injuries, surgical rehabilitation,occupational therapy, and assisted rehabilitation following neural ormuscular injury. For instance, following an injury to a joint or muscle,there is often increased inflammation and scar tissue in the region anddecreased neural and muscular response. Typically, ultrasound isprovided to the affected region to increase blood flow to the region andincrease the metabolic re-absorption of the scar tissue while electricalstimulation is provided separately to the nerves and muscles; however,by providing them together, a person could receive the benefit of eachindividual effect, but additionally amplified stimulatory and metaboliceffects through the altered currents. The other methods for generatingaltered currents discussed within could also be used to assist inphysical therapy via the displacement currents that are generated.

Furthermore, the method according to the present disclosure may beapplied to the area of cellular metabolism, where currents could be usedto interact with electrically receptive cells or charged membranes toalter the tissue or cellular dynamics. It is envisioned that thisembodiment could provide treatment for various diseases whereelectrically receptive cells respond to the newly generated displacementcurrents and altered current distribution.

Furthermore, the method according to the present disclosure may beapplied to the area of gene therapy. Amplified, focused, directionaltered, and/or attenuated currents could be used to interact withelectrically receptive cells or receptors within the cell to influenceprotein transcription processes and alter the genetic content of thecells. The altered current densities in the tissue can interact with thetissue to stimulate this altered gene regulation. Additionally, thedisplacement currents generated by the method could further be used toassist in drug delivery and/or gene therapy through the altered currentinfluence on the delivery of agents.

Furthermore, the method according to the present disclosure may beapplied to the area of tissue growth. Combined energies could be used tointeract with cells or receptors within the cell to influence cellgrowth (and/or tissue(s)) and/or alter cellular (and/or tissue(s))processes and/or structures. Stimulation can be used to increase and orslow cell and/or tissue growth and/or affect tumors, such as throughablation methods whereby energies can be used to ablate tissues or withmethods whereby combined energies can create tumor treating fields. Forinstance, with electromechanical stimulation, altered electromagneticfields generated via electromechanical coupling can affect the tissues,while in certain embodiments the mechanical fields could also have afurther therapeutic effect.

The methods and devices of this disclosure involve providing a firsttype of energy to a region of tissue, in which the first type isprovided in an amount that inhibits cellular function within the regionof tissue, and providing a second type of energy to the region oftissue, in which the second type is provided in an amount thatfacilitates cellular function within the region of tissue, wherein thecombined effect stimulates cellular function within the tissue. Incertain embodiments, the stimulatory effect is facilitatory to thecellular function within the tissue (and in certain embodiments, thestimulatory effect can have a greater facilitatory effect than that ofthe second type of energy alone). In other embodiments, the stimulatoryeffect is inhibitory to the cellular function within the tissue (and incertain embodiments, the stimulatory effect can have a greaterinhibitory effect than that of the first type of energy alone). Forexample, providing one energy type with specific parameters inhibitscertain electrical, thermal, mechanical, optical, and/or chemicalfunctions of a cell (such as in size and/or timing), yet the applicationof a second energy type with specific parameters facilitates certainelectrical, thermal, mechanical, optical, and/or chemical functions of acell, but the combined application of the energies leads to aninhibitory effect(s) greater than the first energy applied alone or afacilitatory effect(s) greater than the second energy type appliedalone. The stimulation can be applied to affect multiple functions ofthe cell, whereby the combined energies could have multiple facilitatoryand/or inhibitory effects on the cell (and/or the individual energiescan have their own independent effects). Furthermore the methodsdescribed herein could be applied to extend (or decrease) the durationof stimulatory effect of one (or both) of the energy types on cellularfunction, whereby the combined effects of the two energies lead to anextended duration of effect of one (or both) of the stimulatoryenergies.

The direction of cellular effect (inhibitory or facilitatory) can becontrolled by any of the energy types applied, depending on the energysource parameters and the targeted tissue. For example with atranscranial DC electrical energy source applied in conjunction with atranscranial ultrasound energy source (such as might be used for imagingor stimulation), the DC electrical energy source characteristics couldbe used to determine the direction of typical cellular response duringtranscranial application (i.e., the polarity of the electrical field);for example one could apply a DC electrical field in conjunction withany typical ultrasound field transcranially to a neural target in thebrain, where the DC electrical field and the ultrasound field could beprovided in either a facilitatory or inhibitory manner, but the DCelectric field is used determine the direction of stimulatory effect,such as could be done with a tDCS stimulation device in conjunction withan ultrasound imaging system, where the polarity of the tDCS fields areused for controlling the direction of combined effect. For instance ifone provided a DC electrical field (such as what could be donetranscranially from an anodal scalp electrode (with approximately 2mA/25 cm̂2 current density amplitude, as reported at the scalp source))focused on the visual cortex while simultaneously providing anultrasound stimulation with inhibitory properties to the same area (suchas could be done with an ultrasound source providing a typicaltranscranial imaging signal of approximately a 2.4 MHz center frequency(where the center frequency refers to the NEMA center frequency,calculated in accordance with NEMA UD2 (NEMA Acoustic Output MeasurementStandard) defined as Fc=(f1+f2)/2 where f1 and f2 are the frequencies atwhich the transmitted acoustic pressure spectrum is 71% (−3 dB) of itsmaximum value), with a Max Ispta.3 of ˜0.2 W/cm̂2 (the derated (at 0.3dB/cm.MHz) Spatial-Peak Temporal-Average intensity (mW/cm̂2)), the MaxIsppa.3 of ˜33 W/cm̂2 (the derated (at 0.3 dB/cm.MHz) Spatial-PeakPulse-Average intensity (W/cm²)), and a Max Imax.3 of ˜46 W/cm̂2 (thederated (at 0.3 dB/cm.MHz) maximum half-cycle intensity value acquiredat the depth where Pii.3 is maximized (W/cm̂2))) the overall effect onthe neural target would be facilitatory (although the techniquesprovided individually would elicit facilitatory (tDCS) and inhibitory(ultrasound) effects). However, by altering the relative position of theDC source (such as by placing it inside the brain) and both lowering itsstrength and reversing its polarity, such that it was a cathodal source(for further examples describing anodal vs cathodal effects see (Wagner,Valero-Cabre and Pascual-Leone, Noninvasive Human Brain Stimulation,Annu Rev Biomed Eng, 2007) or its references (Bindman, Lippold andRedfearn, The Action of Brief Polarizing Currents on the Cerebral Cortexof the Rat (1) During Current Flow and (2) in the Production ofLong-Lasting after-Effects, J Physiol, 172,(369-82, 1964), (Bindman L J,Long-lasting changes in the level of the electrical activity of thecerebral cortex produced by polarizing currents, Nature 196,(584-85,1962), (Purpura and McMurtry, Intracellular Activities and EvokedPotential Changes During Polarization of Motor Cortex, J Neurophysiol,28,(166-85, 1965), and (Terzuolo and Bullock, Measurement of ImposedVoltage Gradient Adequate to Modulate Neuronal Firing, Proc Natl AcadSci USA, 42,(9), 687-694, 1956)), the relative electric field effect onthe visual cortex would be the same as having used the anodalstimulation on the scalp surface (and thus the combined effect would bethe same, but driven by the cathodal driven electric field (but wherethe relative field effects are the same)). However, by flipping thepolarity of the electrical source field in either example the combinedeffects would no longer be facilitatory, but inhibitory. (Although thegeneral convention in transcranial brain stimulation methods is reportedusing the energy source positions on the scalp, one ultimatelydetermines the direction of stimulation of the combined fields byaccounting for the energy fields at the site of action (i.e., thestimulatory field(s) direction and timing at the site of the stimulatedcell(s)) and thus while providing specific examples herein oftranscranial applications (where we generally follow convention ofreporting the effects relative from the scalp application site), theamplitude, source location, timing, and/or vector orientation of theenergy fields (and direction of neural effect (i.e., inhibitory orfacilitatory) can be modified by changing the location and/orcharacteristics of the stimulation energy source(s) (and their appliedenergies)).

And while above we provide an example for combined electrical andmechanical stimulation where the DC electric field is used to controlthe direction of effect (i.e., inhibitor/facilitatory), the relativeinteractions between the two energy types can be used to determine andcontrol the stimulatory effect direction. For instance, one could alsoalter the ultrasound parameters instead of the electrical sourcecharacteristics to control the direction of neural effect (such as onecould provide a DC electric field, but alter the direction of neuralresponse (i.e., inhibitor/facilitatory) through the pulse shape, pulsefrequency, spectral components, and/or relative direction of themechanical fields provided by the ultrasound source (relative to the DCfield)). For example, one could provide an electrical field, such asthrough a DC current source which was inhibitory to the neural targets(such as a cathodal application of a low intensity current to the cortexfrom a scalp electrode overlying the entire scalp (and thus cortex) withan indifferent electrode placed below the mouth of the individual beingstimulated) but also provide a pulsed transcranial ultrasonic field to afocused target in the presence of the broad field (for example with a0.7 MHz field, pulsed on and off (for short pulse durations, for examplefor a period shorter than the refractory period of the targeted cells,or for instance at a 65 microsecond duration, or just for one quarter ofa wave-cycle) at a frequency greater than 20 Hz) to the same brain area.The coupling of the fields can lead to an amplified electrical currentin the tissue (at the frequency in which the ultrasonic field is turnedon and off), which can ultimately have a facilitatory effect on theneural targets, such as for example those in the motor cortex (one canprovide the electric field at an intensity where its effects alone arenegligible in the targeted region, or at a level where the combinedeffects are greater than that of its individual effects). As anotherexample, one could provide the same electrical field, but alter themechanical field such that it is pulsed on and off at a 1 Hz frequency,this in turn would lead to an overall inhibitory effect on the neuraltargets.

Furthermore, one could vary both of the electrical and mechanical fields(e.g., the relative timing, phase, frequency (pulse or spectral power ofindividual pulses), shape, dynamics, direction, and/or amplitude of theapplied energy fields), such as with a control device and/or methodologywhereby the field parameters are controlled and/or tuned to the desiredeffect (facilitatory or inhibitory (and magnitude of effect, timing ofeffect, duration of effect)) based on the combined field analysisrelative to the neural response. These parameters could be alteredcontinuously, whereby combined effects (that when provided individuallycould have contrasting effects) provide stimulatory effects that aregreater than either of the individual modality applied individually.

Ultimately, one could calculate, optimize, tune, or guide the combinedenergy field effects (such as those driven by an electric field sourceand a mechanical field source) with any computational method such asthose explained co-owned and co-pending U.S. patent application Ser. No.13/216,282 the content of which is incorporated by reference herein inits entirety (and/or integrated with imaging data and/or tissue propertydata and/or feedback information, such as those explained co-owned andco-pending U.S. patent application Ser. No. 13/162,047 the content ofwhich is incorporated by reference herein in its entirety).

In another potential embodiment these methods could be implemented toeffectively provide ‘noise’ to the cellular system that is targeted, orprovide continuously alternating inhibitory and facilitatory signals toalter normal cellular function (either with combined stimulatory methods(i.e., multiple energy types) and/or with individual energy types).

All of the methods and processes discussed in this document could beimplemented with any form of stimulation, including but not limited toelectromagnetic, mechanical, optical, thermal, electrical, magnetic,and/or combined methods (and/or methods which alter tissue impedancesrelative to electrical sources to generate altered stimulation currents,for example with electromagnetic, chemical, mechanical, optical,thermal, electrical, magnetic, and/or combined sources). Typically, thetwo energy components would be simultaneously applied; but, using oneenergy type to prime the tissue for one or more energy types is alsopossible, either sequentually applying the energies or with a period oftime in between the second energy application.

Furthermore the methods demonstrated herein could be extended to workwith more than just two energy types, and the direction of effect(inhibitory or facilitatory) determined via the combined energy analysisworking through the different permutations as described above. As in theother methods with two energy types, the dynamics of the energysource(s) could be altered in a manner to controll direction (e.g.,inhibitory, facilitroy) of the combined effect on cellular function. Asin the other methods with two energy types, the direction of the neuraleffect with more than two energy types can be determined by the methodsoutlined herein in conjunction with co-pending and co-owned U.S. patentapplication Ser. No. 13/216,282.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

Equivalents

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein.

EXAMPLES Example 1 Combination of Inhibitory and Facilitatory Amounts ofEnergy

Electrophysiology protocols focused on comparing the combined localvisual evoked potentials (VEP) recorded from a 23 contact electrode,implanted in area 17 (i.e., primary visual cortices, V1) ofanaesthetized adult cats (n=6) during and immediately followingtranscranial stimulations applied to the V1. Application of a mechanicalfield (TUS (2.4 MHz/0.2 W/cm²)), an electrical field (tDCS (2 mA DC/9cm², anodal)), a combination of a mechanical field and an electricalfield (ESSstim (2 mA DC/9 cm², 2.4 MHz/0.2 W/cm²)), and a SHAM (inactivetransducer) were evaluated (i.e., stimulations completed transcraniallyfrom an anodal scalp electrode (with a ˜2 mA/9 cm̂2 current densityamplitude, as reported at the scalp source) and a ultrasound scalpsource (a 2.4 MHz center frequency (where the center frequency refers tothe NEMA center frequency, calculated in accordance with NEMA UD2 (NEMAAcoustic Output Measurement Standard) defined as Fc=(f1+f2)/2 where f1and f2 are the frequencies at which the transmitted acoustic pressurespectrum is 71% (−3 dB) of its maximum value), with a Max Ispta.3 of˜0.2 W/cm̂2 (the derated (at 0.3 dB/cm.MHz) Spatial-Peak Temporal-Averageintensity (mW/cm̂2)), the Max Isppa.3 of ˜33 W/cm̂2 (the derated (at 0.3dB/cm.MHz) Spatial-Peak Pulse-Average intensity (W/cm²)), and a MaxImax.3 of ˜46 W/cm̂2 (the derated (at 0.3 dB/cm.MHz) maximum half-cycleintensity value acquired at the depth where Pii.3 is maximized(W/cm̂2))). Dosing was applied for 5 min periods. Although anesthesia andlow stimulation doses were used to minimize the offline/carryovereffects of stimulation, each application of stimulation was followed bya variable washout period, where the real-time VEP response wasmonitored and allowed to return to the range of the pre-stimulation VEPs(15 min minimum, assessed in 5 min blocks).

A 3-way ANOVA (Dependent: Area Under VEP Curve (i.e., measure ofcortical excitability); Independent: Stimulation Type, Time, and Cat)demonstrated a highly significant effect of stimulation type(F_(3,14699)=73.97, p≈0), time (analyzed in 5 minute epochs (i.e.,online, 0-5, 5-10, and 10-15 mins)) (F_(3,14699)=90.68, p≈0), and cat(F_(5,14699)=40.31, p≈0). A subsequent comparison of the means (with aleast squares difference (LSD) correction, with p set as p<0.05),demonstrated a significant difference between all of the techniquesduring their online periods. It was observed that application of themechanical field alone had a suppressive effect on cellular functionwithin the region of tissue, and that application of the electric fieldhad a facilitatory effect on cellular function within the region oftissue. See FIG. 6A-C. It was observed that combining the mechanicalfield and the electrical field at the same dosing as they were appliedindividually facilitated cellular function within the tissue, and thatthe stimulation of cellular function was approximately 4 times greaterthan the stimulation of cellular function observed from the electricalfield alone. See FIG. 6A-C.

A secondary analysis of the techniques as a function of stimulationtype, time, and contact depth (F_(367,14388)=3.24, p≈0) accounting forcat to cat variability was undertaken where a multiple comparison ofmeans, with an LSD correction(p<0.05), demonstrated the online effectsof the combination of the mechanical field and the electrical field tobe significant throughout every contact (from surface to deepercontacts) and the electrical field to only be significant at thecortical surface. The mechanical field alone had an insignificant effectat any individual contact site but was consistently suppressive (SeeFIG. 6A-C).

Finally, in a sub cat group (n=3 complete), randomized transcranialstimulations to the V1, the frontal eye field (A6), and the posteriormiddle suprasylvian sulcus (PMS) areas have been made with comparisonsbeing made among a combination of a mechanical field and electricalfield, an electrical field alone, a mechanical field alone, and a SHAMfield (i.e., inactive transducers). In these animals, the resultsdemonstrated V1 and PMS stimulation effects similar to above (with theV1 stimulations demonstrating a slightly larger effect than PMS,although not greatly different); and in the deepest target (A6), thecombination of the mechanical field and the electrical field was theonly technique to demonstrate any consistent effect in neural activity(approximately +5.8% change in the VEP magnitude).

1-35. (canceled)
 36. A method for stimulating cellular function withintissue, the method comprising: providing an electrical type of energy toa location in a region of tissue; and providing a non-electrical type ofenergy to the location in the region of tissue; wherein one type isprovided in an amount that inhibits cellular function within thelocation in the region of tissue, the other type is provided in anamount that facilitates cellular function within the location in theregion of tissue, and the combined effect stimulates cellular functionwithin the tissue in a manner in which the stimulatory effect exceedsthe combined effect of the two amounts of energy provided to the regionof tissue.
 37. The method according to claim 36, wherein the stimulatoryeffect is facilitatory to the cellular function within the tissue. 38.The method according to claim 36, wherein the stimulatory effect isinhibitory to the cellular function within the tissue.
 39. The methodaccording to claim 36, wherein the electrical and non-electrical typesare provided simultaneously.
 40. The method according to claim 36,wherein the electrical and non-electrical types are providedsequentially.
 41. The method according to claim 36, wherein thenon-electrical type of energy is a mechanical type of energy.
 42. Themethod according to claim 41, wherein the mechanical type of energy isgenerated by an ultrasound device.
 43. The method according to claim 42,wherein the mechanical type of energy is pulsed.
 44. The methodaccording to claim 42, wherein the mechanical type of energy is timevarying.
 45. The method according to claim 42, wherein the mechanicaltype of energy is pulsed a plurality of time, and each pulse may be fora different length of time.
 46. The method according to claim 36,wherein the electric type of energy is pulsed.
 47. The method accordingto claim 36, wherein the electric type of energy is time varying. 48.The method according to claim 36, wherein the electric type of energy ispulsed a plurality of time, and each pulse may be for a different lengthof time.
 49. The method according to claim 36, wherein the electric typeof energy is time invariant.
 50. The method according to claim 36,wherein the electrical and non-electrical types of energy are applied toa structure or multiple structures within the brain or the nervoussystem selected from the group consisting of: dorsal lateral prefrontalcortex, any component of the basal ganglia, nucleus accumbens, gastricnuclei, brainstem, thalamus, inferior colliculus, superior colliculus,periaqueductal gray, primary motor cortex, supplementary motor cortex,occipital lobe, Brodmann areas 1-48, primary sensory cortex, primaryvisual cortex, primary auditory cortex, amygdala, hippocampus, cochlea,cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe,parietal lobe, sub-cortical structures, and spinal cord.
 51. The methodaccording to claim 36, wherein the tissue is neural tissue.
 52. Themethod according to claim 51, wherein the effect of the stimulationalters neural function past the duration of stimulation.